1. Field of the Invention
This invention relates to a sampling and/or dispensing method and apparatus for performing the same. There are many occasions where body fluid samples have to be collected by first piercing the skin and then sampling a fluid, such as blood or interstitial fluid (ISF), or cells contained within. A very important application is the sampling of blood or ISF for various analyses, for example blood glucose, electrolytes or cholesterol. In some applications, for example in the use of Point of Care (POC) instruments, it is important to provide an accurately metered sample of fluid to the instrument. There are also advantages to being able to deposit a fluid (for example antiseptic) on the skin before making an incision.
2. Related art
The most commonly used blood sampling devices are the hypodermic syringe and lancet. Taking a blood sample by either of these methods can be painful for the patient/subject, and can cause distress, particularly in the case of diabetes sufferers who may have to take several blood samples a day. It is for this reason that there has been a trend towards taking smaller quantities of blood and the use of smaller devices penetrating the skin to a lesser depth. Disposable lancets are the commonly preferred devices for puncturing the skin for blood glucose measurement.
Taking a blood sample is only one part of the process. The sample then has to be transferred to a system for analysis. In the case of blood glucose monitoring, a lancet is used to puncture the skin and is then withdrawn. A blood droplet then forms on the surface of the skin and is transferred by capillary or wick to a test strip. This involves the use of several devices in separate steps. Many test devices are used by the subjects themselves rather than by medical staff, so it is important that the whole process is performed accurately with the minimum of user intervention. It is also important to minimise the risk of contamination to the user, and to third parties who could come into contact with sharps contaminated with blood.
In POC testing, the POC instrument is often a bench-top instrument and cannot be taken to the patient, for example, to take a sample of blood from a patient. In such circumstances it is necessary to take a sample of blood or ISF and transfer such to the instrument. It is further desirable that either the sample itself or the dispensed aliquot of the sample be of an accurately measured volume to ensure accuracy of the resulting test.
The prior art in blood sampling describes devices for combining lancing and fluid sampling. U.S. Pat. No. 4,360,016 discloses a capillary channel adjacent and parallel to a lancet. After withdrawing the lancet from the skin, a droplet of blood may fill the capillary by capillary action. WO2004/066822 describes the combination of a lancet and blood glucose test strip with a capillary channel adjacent the tip of the lancet. WO2004/066822 improves upon U.S. Pat. No. 4,360,016 by delivering blood directly to a glucose test strip by capillary action.
WO02/100254 discloses another approach, where a capillary channel is provided with an entrance adjacent a housing containing a lancet, the capillary channel being arranged at an angle to the lancet. A droplet of blood in proximity to the lancet can be drawn by capillary action into the capillary. WO02/056751 describes a lancet within a housing that forms an annular capillary channel concentrically around the lancet between the lancet and the housing. WO2004/060163 also describes a lancet within a capillary tube member such that the clearance between the lancet and housing forms an annular capillary.
Yet another method of capillary sampling is to provide a hollow microneedle in connection with a capillary such that the whole assembly forms a capillary sampling conduit. This may further be integrated with blood glucose sensing. Examples in the prior art include US2004/0096959 and US2003/0153900.
US2004/122339 offers an improvement in fluid flow in capillaries by control of the dimensions and surface energy of the capillary channel. EP1491144 describes a system for sampling ISF. This system includes pressure rings to encourage flow of ISF into the device. The device employs sampling by capillary action.
The present inventors have realised that capillary-based sampling systems work well for many applications, but they do have the disadvantages that there is no control over the timing and rate of sampling once the capillary is presented to the sample; liquid generally will not flow from a narrow diameter capillary to a capillary or sensor chamber of larger diameter; they cannot deliver a fluid to the skin before lancing; most configurations have no provision for ejecting a sample; and they cannot be reversed to eject, deposit or re-take a sample.
US2003/0088191 describes a lancet attached to a diaphragm. Air pressure behind the diaphragm is used to drive the lancet tip out of an orifice to pierce the skin. Applying a partial vacuum behind the diaphragm serves to withdraw the lancet and create a negative pressure in a chamber to draw in a fluid sample. The device of US2003/0088191 is intended to sample blood for blood gas analysis in such a way that the sample does not come in contact with air that could contaminate the sample for the intended analysis. It is therefore designed to seal against the skin. The device is provided with two mechanically actuated valves to enable the device to act as a diaphragm pump to suck blood from a wound through a first orifice and deliver it through a second orifice to an external device, such as a blood gas analyser. The device has disadvantages for application to blood sampling for blood glucose determination and POC. The lancet must be fully extended to attempt to eject all the contents, and thus presents a risk of injury.
The device of US2003/0088191 is also not suitable for the procedure of first lancing the subject's skin, allowing a droplet of blood to collect on the skin and then aspirating the droplet of blood. (As will be seen, this is one aspect of the present invention, set out in detail later.) This is because the lancet has to be extended to permit aspiration without admitting a significant volume of air. The device is also not particularly suited to delivering a small sample of blood back out through the original sampling orifice. Depending on the orientation of the device, air within the chamber may push past the blood and exit instead of or before the blood sample when the device is reversed to dispense the sample. The use of a diaphragm driven by air and the compressibility of the air headspace can make it very difficult to exert close control over the sampling and dispensing volumes. The device of US2003/0088191 is therefore most suited to its intended application of aspirating an approximate volume of blood in the absence of air and transferring part of that volume to another external blood gas analyser. The transferred volume is unlikely to be of high precision.
U.S. Pat. No. 5,569,287 discloses a blood sampling device utilising a trigger mechanism to push a needle into a puncture position by operation of a piston. Sampling of a blood drop is achieved by withdrawing the piston along its barrel, creating a partial vacuum in a headspace above the blood drop, drawing a blood sample into tube surrounding the needle. The separation of the piston and sample has the disadvantage that it is difficult or impossible accurately to meter the volume of blood drawn into the device. Additionally, the trigger mechanism ensures that forward displacement (at least) of the needle does not occur in fixed relation to movement of the piston.
Another group of prior art devices are the devices that employ suction to draw blood to the surface of an incision. The purpose of these is to help to draw blood to the surface at “alternative testing sites”, such as the arms or legs, that are less painful than the fingers, but are more difficult to draw blood from. U.S. Pat. No. 4,653,513 describes a system having a lancet attached to a plunger. The plunger is provided with a piston seal and moves within a parallel bore. The forward end of the bore is provided with a gasket to seal onto the skin of the user when pressed firmly in contact. The lancet and plunger are driven down together to pierce the skin and then fully retracted under spring force to create a partial vacuum in the bore. The purpose of this device is to apply suction around the lanced incision to create a droplet of blood on the surface of the skin. The blood droplet remains on the skin and is sampled by another device when the suction device has been removed. The device of U.S. Pat. No. 4,653,513 cannot aspirate or contain a blood sample and has no provision for doing so.
U.S. Pat. No. 5,368,047 describes an improvement over U.S. Pat. No. 4,653,513 containing a separate lancet and plunger. The inventor describes a disadvantage of U.S. Pat. No. 4,653,513, where the friction of the piston seal in the device is detrimental to the lancing action. U.S. Pat. No. 5,369,047 solves this problem by providing a low friction lancet that does not seal at any point in the bore, and a separate syringe assembly at the other end of the device to create a vacuum. Three integral springs are used to drive the device. Once again, the device is designed to cause a sessile drop of blood to form on the surface of the skin for another system to sample from, and has no provision for aspiration or containment of the blood sample within the lancing device described. Further examples of this type of device are provided in U.S. Pat. No. 2002/111565 and WO9955232. The figures contained in WO9955232 are particularly useful in demonstrating how suction devices encourage a droplet of blood to be drawn to the skin surface by applying vacuum to the wound site and thereby allow for subsequent sampling by another device.
The present inventors have realised that it may be desirable in some cases to be able to deliver a fluid to the site of the incision before the incision is made. Such fluid may be for example an antiseptic to prevent infection or an anaesthetic to reduce the pain of incision. This would be a useful function for a blood sampling system. It may also be desirable that a fluid be delivered to the skin that has a diagnostic function, for example the use of allergens to diagnose allergies.
It is now common practice in doctors surgeries or allergy clinics to test patients complaining of allergic reactions such as urticarial rashes for sensitivity to common allergens such as house dust, moulds, dairy products, etc, by dispensing a drop of liquid containing one such allergen to the skin surface and lancing the skin through the dispensed drop of liquid. It is not necessary to lance the skin deeply for this test, as the intent is to damage the skin and provoke a histamine-mediated inflammation reaction, rather than produce a sample of blood at the puncture site.
If an allergic reaction occurs to the allergen present at the puncture site, this is evidenced by a histamine-induced localised swelling of the skin at the puncture site that creates a defined circular patch of raised, inflamed skin within 10 minutes of the puncture. The size of the weal or swelling produced at the puncture site after 10 minutes is an indication of the severity of the allergic reaction. In current practice for skin-prick allergy tests, a negative control is normally provided by substituting distilled water for allergen solution, where no appreciable swelling would be expected. A positive control is normally provided by substituting dilute histamine solution for allergen solution. This should result in significant swelling at the puncture site.
It is common practice in allergy testing to make an array of such punctures on the skin of the forearm as quickly as possible so that the time between the first and last puncture of the series is a short as possible, and also to label or mark the skin adjacent to each puncture site to record which allergen was used at which puncture site.
Commercial lancet devices are available to delivering allergens to the skin before piercing the skin. Examples include the Quintip™ from Hollister Steer Laboratories LLP, and the GreerPick™ from Greer Laboratories. These devices employ surface tension passively to pick up an allergen solution from an open reservoir for transfer to the skin and an integral lancet to pierce the skin.
The prior art discloses several arrangements involving the use of microneedles to deliver fluids beneath the skin by a minimally invasive method. Examples of microneedle devices and arrays for fluid delivery can be found in US2005/143713, US2005/137525, WO2005/049107, WO2003/022330 and CN1562402. Such microneedle systems are designed to deliver a fluid beneath the skin through an incision, not to deliver a fluid to the skin before incision. Microneedles are generally more invasive than lancets because the needle has to be of sufficient diameter to be hollow.
The present inventors therefore consider that it is thus desirable to be able to perform any or a combination of some or all of the actions of fluid delivery, piercing, sample collection, sample transfer and analysis using a single device. The damage to tissue and the pain experienced by the subject is also known to be related to the diameter of the lancet or hypodermic needle. It is therefore also desirable that the cross-sectional area of the skin piercing component of the sampling device is minimised.
Efficient liquid sampling and depositing systems in the form of laboratory pipetting systems are known. U.S. Pat. No. 5,413,006 and EP0364621 represent typical examples of air-displacement pipettors with separate pipette tips. EP0078724 describes a hand-held positive displacement pipettor with disposable tips. EP1212138 describes a miniaturised positive-displacement pipette capable of aspirating and dispensing sub-microliter volumes of liquid, while WO0112330 describes how such pipettes may be attached to a continuous strip for automated pipetting. These devices can aspirate and dispense fluids to high accuracy, but have no capability to pierce the skin or to affect an analysis.